EP0007615B1 - Verfahren zur Herstellung von Aminosäuren und Estern - Google Patents
Verfahren zur Herstellung von Aminosäuren und Estern Download PDFInfo
- Publication number
- EP0007615B1 EP0007615B1 EP79102617A EP79102617A EP0007615B1 EP 0007615 B1 EP0007615 B1 EP 0007615B1 EP 79102617 A EP79102617 A EP 79102617A EP 79102617 A EP79102617 A EP 79102617A EP 0007615 B1 EP0007615 B1 EP 0007615B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- methyl ester
- formula
- phenyl
- procedure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 0 CC(/C=C1)C#CC#CC1(C)ONCN=* Chemical compound CC(/C=C1)C#CC#CC1(C)ONCN=* 0.000 description 2
- NPHFOFOYWYLBTF-UHFFFAOYSA-N Cc(c1c2)c[nH]c1ccc2O Chemical compound Cc(c1c2)c[nH]c1ccc2O NPHFOFOYWYLBTF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Definitions
- the present invention is concerned with an efficient process for preparing a-vinyl substituent-a-amino acids and esters and certain intermediates.
- a-vinyl-a-amino acids can be prepared by reducing the corresponding ⁇ -ethynyl ⁇ -amino acid. Such processes are described in Tetrahedron Lett. 2745-2748; 3689-3692 (1977).
- J.C.S. Chem Communication No. 4 (1977), 125 discloses compounds of formula (2) similar to the N-benzylididne-2-amino crotonic acid esters which are used as starting compounds in the process of the invention.
- An embodiment of the present invention is a process for preparing compounds having the formula: which comprises (a) treating a compound of the formula: with a strong amine base, (b) reacting the product from (a) with an alkylating agent, R 3 X, or and (c) hydrolyzing the product from (b), wherein R is alkyl, alkenyl or substituted alkyl, R 1 is H or lower alkyl, R 2 is the residue of an aldehyde of the formula R 2 CHO having no a-hydrogen, where R 2 is a phenyl or substituted phenyl group wherein the substituents are halo (Cl, Br or I), C 1-3 alkyl or NO 2 , R 3 is alkyl, alkenyl or substituted alkyl, R 4 is alkyl- substituted alkyl- or aryl-sulfonyl, R 5 is alkyl, aryl or alkaryl and X is Cl, Br or I.
- R is an alkyl, substituted alkyl or alkenyl group.
- Preferred R substituents are selected from the group consisting of: Especially preferred R groups are or
- R' is preferably a lower C 1 ⁇ C 3 , alkyl group, such as octyl, hexyl, pentyl, isopropyl, ethyl or methyl.
- Preferred R 1 groups are C 1 ⁇ C 6 alkyl.
- a most preferred R 1 group is methyl.
- R 2 is the residue of an aldehyde of formula R 2 CHO, having no a-hydrogen, where R 2 is a phenyl or substituted phenyl group wherein the substituents are halo (Cl, Br or I) C 1 ⁇ C 3 alkyl or NO 2 .
- R 2 groups are phenyl, p-chlorophenyl, 4-nitrophenyl and 4-isopropylphenyl.
- a preferred R 2 group is phenyl.
- R 3 is an alkyl, alkenyl or substituted alkyl group which is the same as or readily convertible to the R group.
- Readily convertible R 3 groups are R groups which bear OH groups and are protected. Examples of such protected moieties are and Z is H, lower alkyl e.g. CH 3 or butyl, phenyl or substituted phenyl e.g. p-CH 3- phenyl.
- a preferred Z group is phenyl.
- R 4 is an alkyl, substituted alkyl or aryl sulfonyl group such as p-toluenesulfonyl, benzenesulfonyl, nitrophenylsulfonyl, chlorophenylsulfonyl and hexylsulfonyl.
- X is halo e.g. Br, Cl or I. Chloro is preferred.
- R 5 is a C,-C s alkyl group e.g. CH 3 , pentyl or isopropyl; an aryl group such as phenyl, bromophenyl, p-totyl and xylyl; an aralkyl group such as benzyl.
- a preferred R 5 group is the C,-C 5 alkyl moiety, especially methyl.
- the Schiff base (a) is conveniently prepared from A-chloro-a-amino butyric methyl ester hydrochloride using the process described in Helv. Chem Acta 40, 1531 (1957).
- the strong base in Step A may be a suitable lithium dialkylamide.
- bases are lithium diisopropylamide, lithium dimethylamide and lithium dicyclohexylamide and lithium hexamethyldisilazide.
- a preferred base is lithium hexamethyldisilazide.
- the liquid reaction medium used for step A is preferably an aprotic medium such as hexamethyl- phospharamide (HMPA)m tetrahydrofuran (THF), ethyl ether and 1,4-dioxane.
- HMPA hexamethyl- phospharamide
- THF tetrahydrofuran
- ethyl ether 1,4-dioxane.
- a preferred medium is HMPA and THF.
- Step A is carried out at temperatures ranging from about -70°C to about room temperature.
- step B is carried out directly on the step A reaction product.
- step B the (b) compound is treated with an appropriate alkylating agent as defined above.
- the alkylating agent is added directly to the reaction product (b) in said liquid reaction medium.
- Step B is carried out at temperatures ranging from about 70°C to room temperature.
- the ester (d) is then hydrolyzed using a suitable inorganic acid to produce the final product (e) as the acid salt.
- the hydrolysis step also serves to remove any other blocking groups, e.g., the hydroxyl blocking group present in the R 3 moiety.
- the final product (e) may be converted to the free base by conventional neutralization.
- a preferred intermediate used in the inventive process has the formula:
- the Formula I products have pharmaceutical activity, e.g., as enzyme inhibitors, antihypertensive agents, antitumor agents and antiallergics.
- a solution of lithium hexamethyldisilazide was prepared by adding 5.5 mmol of butyllithium (2.2 M solution in hexane) to a cooled (-70°C) solution of 1.15 ml of hexamethyldisilazane in 12.5 ml of tetrahydrofuran. To this solution was added first 3.5 ml of hexamethylphosphoramide and then a solution of 1.15 g of N-benzylidine-2-aminocrotonic acid methyl ester in 12.5 ml of tetrahydrofuran.
- Example 1B alkylation was carried out with N-benzylidine-3-amino-1-bromopropane.
- the crude product was mixed with 100 ml. of 6N hydrochloric acid and the well-stirred mixture was heated at 110°C. for 2 hours.
- the solution was cooled, extracted four times with 10 ml. of methylene chloride, and treated with activated charcoal.
- the solution was filtered and evaporated, and the residue purified on DOWEX 50W-X4 cation exchange resin, eluted first with water and then with 2N hydrochloric acid, giving 0.560 g.
- DOWEX 50W-X4 cation exchange resin elution with water and then 2N aqueous hydrochloric acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Claims (7)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT79102617T ATE1189T1 (de) | 1978-07-24 | 1979-07-24 | Verfahren zur herstellung von aminosaeuren und estern. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US92720978A | 1978-07-24 | 1978-07-24 | |
US927209 | 2001-08-10 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0007615A2 EP0007615A2 (de) | 1980-02-06 |
EP0007615A3 EP0007615A3 (en) | 1980-05-28 |
EP0007615B1 true EP0007615B1 (de) | 1982-06-16 |
Family
ID=25454396
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP79102617A Expired EP0007615B1 (de) | 1978-07-24 | 1979-07-24 | Verfahren zur Herstellung von Aminosäuren und Estern |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0007615B1 (de) |
JP (1) | JPS5519281A (de) |
AT (1) | ATE1189T1 (de) |
DE (1) | DE2963107D1 (de) |
DK (1) | DK309379A (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5245046A (en) * | 1988-11-14 | 1993-09-14 | The Upjohn Company | α-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents |
JPH06507402A (ja) * | 1991-03-20 | 1994-08-25 | ワーナー−ランバート・コンパニー | 治療活性を有するα−置換ポリペプチド |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4401676A (en) * | 1977-06-01 | 1983-08-30 | Merck & Co., Inc. | Novel α-amino acids |
GB2001627B (en) * | 1977-07-01 | 1982-04-28 | Merrell Toraude & Co | Alpha-vinyl and acetylene amino acid derivatives |
US4103089A (en) * | 1977-07-01 | 1978-07-25 | Merrell Toraude Et Compagnie | α-Acetylene and α-vinyl derivatives of amino acids |
CA1157030A (en) * | 1977-07-01 | 1983-11-15 | Brian W. Metcalf | .alpha.-VINYL AMINO ACIDS |
-
1979
- 1979-07-23 DK DK309379A patent/DK309379A/da not_active Application Discontinuation
- 1979-07-24 DE DE7979102617T patent/DE2963107D1/de not_active Expired
- 1979-07-24 EP EP79102617A patent/EP0007615B1/de not_active Expired
- 1979-07-24 JP JP9334579A patent/JPS5519281A/ja active Pending
- 1979-07-24 AT AT79102617T patent/ATE1189T1/de active
Also Published As
Publication number | Publication date |
---|---|
EP0007615A2 (de) | 1980-02-06 |
JPS5519281A (en) | 1980-02-09 |
ATE1189T1 (de) | 1982-07-15 |
EP0007615A3 (en) | 1980-05-28 |
DE2963107D1 (en) | 1982-08-05 |
DK309379A (da) | 1980-01-25 |
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